Herbal compositions useful as chemopreventive and therapeutic agents

ABSTRACT

Composition derived from traditional Chinese herbal medicines, medicinal plants and extracts thereof, are provided. These compositions can be used as chemopreventive and therapeutic agents.

The present invention relates to compositions comprising herbs and theiruse as chemopreventive and therapeutic agents.

BACKGROUND OF THE INVENTION

For the past twenty-five years there has been significant progress inthe field of cancer research; however, in spite of these positiveresults, the mortality rate for the most common cancers still remainshigh. Indeed, the goal of the National Cancer Institute of a fiftypercent reduction in overall cancer mortality by the year 2000 has notbeen met.

The term “cancer” is a general one referring to more than 100 forms ofthe disease which may manifest itself in almost every tissue type of thebody. Of the myriad forms of cancer, lung cancer is the most commoncause of death worldwide, followed by stomach cancer. Other common formsof cancer include cancers of the colon, rectum, breast, prostate, mouthand esophagus.

Lung cancer imposes an enormous burden on health care. The World HealthReport 2000 estimates that lung cancer has resulted in 860,000 deathsamong men and 333,000 deaths among women per year, and it is the leadingcause of cancer deaths worldwide. In the United States and Canada, morepeople are dying from lung cancer than from breast cancer, colorectalcancer and prostate cancer combined. In addition, the incidence of lungcancer in women is rising at an average annual rate of 7% which is themost rapid rate of increase for any cancer. The most dominant cause oflung cancer is tobacco use, but occupational and environmental exposureto various other carcinogenic substances can also influence diseasedevelopment. In long-term smokers, the risk of lung cancer never returnsto the “baseline” level of a never-smoker, even years after smokingcessation. With a large reservoir (100 million in the United States andCanada alone) of current and former smokers, who are at risk, lungcancer will continue to be a major health problem for at least severalmore decades even if current efforts to curb tobacco smoking weresuccessful. The overall five-year survival rate of lung cancer is lessthan 15%. Despite advances in modern medicine, the survival rate has notimproved substantially over the last two decades. A different approachis therefore needed to control lung cancer.

Prostate cancer is the most commonly diagnosed male malignancy in theUnited States and the second leading cause of cancer death. It isestimated that in the year 2000, there will be 180,400 new cases and31,900 deaths caused by prostate cancer. Although prostate cancerresponds effectively to orchitectomy or antiandrogen therapy whendetected at an early stage, over time, the residual androgen-insensitivecells recolonize, expand, and ultimately establish a hormone-resistantstate that often results in fatality. It would be useful, therefore, tohave a cancer treatment which could prevent the proliferation ofprostate cancer and maintain it in a dormant state.

The incidence of gastric cancer has fallen in most countries but it isstill the most common form of cancer in many countries of East Asia,including China. Globally, gastric cancer is the second most frequentcause of cancer death and it is estimated that in 1990, there werealmost 800,000 new cases and about 630,000 deaths. Similarly, esophagealcancer, the eighth most common cancer worldwide and responsible for316,000 new cases and 286,000 deaths in 1990, is also very common inChina and other Asian countries. Both of these cancers, and especiallyesophageal cancer, have low survival rates and thus it would bebeneficial to have an alternative treatment approach for these types ofcancers.

Traditionally, the focus of cancer research has been in developingtherapies and treatments for patients already afflicted with thedisease. However, over the last few decades, new insights into thedevelopment of cancer as a disease have been gained. It is nowunderstood that cancer is not the result of a single initiation eventbut of a gradual, multi-step process characterized by a period ofseveral years between the initiation event and the onset of invasive ormetastatic disease. In general, the process of carcinogenesis can bedivided into three phases: initiation, promotion, and progression. Ininitiation, a fixed genetic mutation results from the interaction of acarcinogen with DNA. The extent of the molecular change depends on anumber of factors including the nature of the carcinogen, the rate andtype of carcinogenic metabolism and the response of the DNA repairsystems. The next phase, promotion, may occur over extended periods oftime and is characterized by the proliferation of the altered cells.This phase may be affected by agents that alter growth rates. During thefinal phase, progression, genetic and phenotypic changes occur whichultimately cause the development of premalignant lesions into invasivecancer.

The multi-step nature of carcinogenesis suggests the possibility ofintervention at a precancerous state. This is the basis forchemoprevention, which refers to the use of natural or synthetic agentsto prevent the development of cancer, either by blocking the DNA damagethat initiates the carcinogenesis process or by arresting/regressingexisting pre-malignant lesions.

Since the mid-1950s, research has been directed at finding compoundswith potential chemopreventive properties. The search for these agentshas demonstrated a unique challenge. Chemopreventive agents must havelow toxicity and be relatively free of side effects because they areintended for administration to healthy people over long periods of time.This is in direct contrast to chemotherapy drugs, such as cis platinumor paclitaxel (Taxol™), which are used as chemotherapeutic agents totreat people already afflicted with cancer. Chemotherapeutic agents arechosen for their ability to kill tumor cells but because they are alsotoxic to healthy cells, they usually cause harmful side effects.

One of the major sources of potential chemopreventive agents is plants.For example, consumption of cruciferous vegetables, such as broccoli,cauliflower and cabbage is associated with a lower risk of variouscancers. Fruits and vegetables contain a number of potentially activechemopreventive compounds, such as carotenoids, dithiolthiones andisothiocyanates. They are capable of inhibiting the development oftumors of the lungs, colon, mammary glands and bladder in laboratoryanimals.

Three proof-of-principle clinical trials suggest that chemopreventionmight be an effective strategy to control lung cancer. A study by Hongand co-workers in the United States showed that in patients with curedhead and neck cancer, high dose 13-cis-retinoic acid for 12 months wasmore effective than placebo in preventing second primary cancers in theupper aerodigestive tract. However, 13-cis-retinoic acid at this dosagecarries unacceptable toxicity for use in the general population. Anotherstudy by Pastorino and co-workers in Europe showed that retinolpalmitate in a dose of 300,000 Units per day for 12 months was moreeffective than placebo in preventing second primary lung cancer. A thirdstudy in China found that daily doses of a combination of vitamins andminerals consisting of beta-carotene, vitamin E and selenium resulted ina 21% decrease in stomach cancer deaths in high-risk people in China.However, subsequent phase III clinical trials using beta-carotene orretinal (the Alpha-Tocopherol, Beta-Carotene Trial, the Beta-Caroteneand Retinol Efficacy Trial, and the EUROSCAN study) failed to show areduction in lung cancer incidence in high-risk individuals, such asheavy smokers with or without exposure to asbestos, compared to placebo.In fact, the use of beta-carotene in those who continued to smoke duringthe study was found to increase the risk of lung cancer. Several reasonswere postulated to explain why chemopreventive treatment with retinoidswas ineffective or even harmful in active smokers. There may be adverseinteractions between tobacco carcinogens and the chemopreventive agent.Beta-carotene, for example, is a pro-oxidant at high arterial oxygentension. It can enhance conversion of benzo[A]pyrene to the ultimatecarcinogen as well as inducing cytochrome P450. Another reason for thelack of effect in active smokers is that ongoing tobacco carcinogenexposure may counteract the effect of the chemopreventive agent.

A number of chemopreventive agents are currently under clinicalinvestigation. Examples of these include fenretinide, selenium, inhaledbudesonide, COX-2 inhibitors, farnesyl transferase inhibitors,lipoxygenase inhibitors, EGF-kinase inhibitors and green tea. Althoughpromising, it remains to be shown if these agents can be shown to beuseful in ongoing clinical trials.

The best example to-date that chemoprevention can prevent cancer isTamoxifen. Tamoxifen is an estrogen antagonist. In women at high risk ofbreast cancer, the Breast Cancer Prevention Trial showed a 49% decreasein invasive cancer and a 50% decrease in non-invasive breast cancer withTamoxifen versus placebo (J Natl Cancer Inst 1998; 90:1371-88). Inaddition, there was a decrease in the incidence of fractures due toosteoporosis. However, there was a slight increase in the risk ofendometrial cancer, deep venous thrombosis and pulmonary embolism. Moreselective estrogen-receptor modulators such as Raloxifene, are beingtested against Tamoxifen to determine if these agents may have similarchemopreventive effect but fewer side effects than Tamoxifen.

A variety of Chinese herbs have been used for centuries to treatdifferent diseases. The great majority of these are empirical, open,non-randomized studies without placebo control groups. Although some ofthese herbs have been used to treat patients with cancer, they are notconsidered to be disease specific. Rather, they are used for “dispersingheat, detoxification, improving stasis and removing mass”. Herbs such asSophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchusbrachyotus, Dictamnus dasycarpus Turcz, and Dioscorea bulbifera areknown to have properties that may be useful for the prevention andtreatment of cancers. One such composition is known as ZSP or Zeng ShengPing; however, the exact formulation of the composition is not known.

European Patent application 93 121109.8 describes a compositioncomprising Sophora tonkinensis Gapnep 42 mg, Polygonum bistorta L. 42mg, Prunella vulgaris L. 42 mg, Sonchus brachyotus DC 42 mg, Dictamnusdasycarpus Turcz 21 mg, and Dioscorea bulbifera 10 mg which was reportedto be useful for the treatment of patients with mouth, esophagus ordigestive tract cancers. Thus, there is a need to develop other herbalremedies for the treatment and prophylaxis of common cancers, and forother therapeutic uses.

SUMMARY OF THE INVENTION

Thus, according to the present invention there is provided a compositioncomprising herbs.

Thus, according to this embodiment of the invention, there is provided acomposition comprising a mixture of at least three different herbsselected from the group consisting of herbs, which for the purpose ofthis invention have been designated as: Herb A, Herb B, Herb C, Herb D,Herb E and Herb F.

In the composition defined in EPO 93121109.8 the herb corresponding toHerb A was Sophora tonkinensis (Sophora subprostrata). According to thepresent invention it has been found that any one of the following herbscan be used in place of Sophora tonkinensis:

Belamcanda chinensis

Scrophularia ningpoensis.

Isatis tinctoria

Isatis indigotica or

Baphicacanthus cusia Bremek.

In the composition defined in EPO 93121109.8 the herb corresponding toHerb B was Polygonum bistorta. According to the present invention it hasbeen found that any one of the following herbs can be used in place ofPolygonum bistorta:

Polygonum lapidosum

Polygonum viviparum

Polygonum manshuriense

Polygonum alopecuroides

Polygonum sphaerostachyum

Andrographis paniculata

Taraxacum mongolicum or

Chrysanthemun indicum.

In the composition defined in EPO 93121109.8 the herb corresponding toHerb C was Prunella vulgaris. According to the present invention it hasbeen found that any one of the following herbs can be used in place ofPrunella vulgaris:

Artemissia capillaris

Gardenia jasminoides

Rosa rugosa or

Lophatherum gracile.

In the composition defined in EPQ 93121109.8 the herb corresponding toHerb D was Sonchus brachyotus. According to the present invention it hasbeen found that any one of the following herbs can be used in place ofSonchus brachyotus:

Patrinia scabiosaefolia

Patrinia villosa

Sonchus arvensis

Thlaspi arvense

Portulaca oleracea or

Pulsatilla chinensis.

In the composition defined in EPO 93121109.8 the herb corresponding toHerb E was Dictamnus dasycarpus. According to the present invention ithas been found that any one of the following herbs can be used in placeof Dictamnus dasycarpus:

Kochia scoparia

Sophora flavescens or

Heydyotis diffusa.

In the composition defined in EPO 93121109.8 the herb corresponding toHerb F was Dioscorea bulbifera. According to the present invention ithas been found that any one of the following herbs can be used in placeof Dioscorea bulbifera:

Panax notoginseng

Bletilla striata

Nelumbo nucifera

Polygonum bistorta

Cephalanoplos segetum

Cirsium japonicum

Sophora japonica

Typha angustifolia. or

Rubia cordifolia.

Further according to the present invention there is provided a use ofsaid composition as chemopreventive and therapeutic agents.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

The present invention relates to compositions comprising herbs and theiruse as chemopreventive and therapeutic agents.

In one embodiment of the present invention the composition comprises amixture of at least three different herbs, known hereinafter as Herb A,Herb B, Herb C, Herb D, Herb E and Herb F.

According to the present invention Herb A is selected from the groupconsisting of: Belamcanda chinensis

Scrophularia ningpoensis

Isatis tinctoria

Isatis indigotica and

Baphicacanthus cusia.

According to the present invention Herb B is selected from the groupconsisting of: Polygonum lapidosum

Polygonum viviparum

Polygonum manshuriense

Polygonum alopecuroides

Polygonum sphaerostachyum.

Andrographis paniculata

Taraxacum mongolicum and

Chrysanthemun indicum.

According to the present invention Herb C is selected from the groupconsisting of: Artemissia capillaris

Gardenia jasminoides

Rosa rugosa and

Lophatherum gracile.

According to the present invention Herb D is selected from the groupconsisting of: Patrinia scabiosaefolia

Patrinia villosa

Sonchus arvensis

Thlaspi arvense

Portulaca oleracea and

Pulsatilla chinensis.

According to the present invention Herb E is selected from the groupconsisting of: Kochia scoparia

Sophora flavescens and

Heydyotis diffusa.

According to the present invention Herb F is selected from the groupconsisting of: Panax notoginseng.

Bletilla striata

Nelumbo nucifera.

Polygonum bistorta

Cephalanoplos segetum.

Cirsium japonicum.

Sophora japonica

Typha angustifolia and

Rubia cordifolia.

When, according to the present invention, the composition comprisesthree different herbs, one of which is selected from each of Herb A,Herb B, Herb C, Herb D or Herb E, each of the three herbs are present inan amount from about 9% to about 57%. In a further example of thisembodiment, the three herbs are each present in an amount from about 15%to about 50%. In a further example of this embodiment, each of the threeherbs are present in an amount from about 25% to about 40%. In a furtherexample of this embodiment, each of the three herbs are present in anamount of about 33%.

When the composition comprises four different herbs, one of which isselected from each of Herb A, Herb B, Herb C, Herb D or Herb E, each ofthe four herbs are present in an amount from about 6% to about 43%. In afurther example of this embodiment, each of the four herbs are presentin an amount from about 15% to about 35%. In a further example of thisembodiment, each of the four herbs are present in an amount of about25%.

In a further example of the present invention, when the compositioncomprises four herbs, three of which are selected from the groupconsisting of Herb A, Herb B, Herb C, Herb D and the fourth herb isselected from the group consisting of Herb E. The composition of thefirst three herbs are each present in an amount from about 7% to about57% and the fourth herb is present in an amount from about 3.5% to about28.5%. In a further example of this embodiment, each of the first threeherbs are present in an amount from about 15% to about 48% and thefourth herb is present in an amount from about 7.5% to about 24%. In afurther example of this embodiment, the first three herbs are present ina composition in an amount of about 20% to about 43%, and the fourthherb is present in an amount from about 10% to about 21.5%. In a furtherexample of this embodiment, the first three herbs are present in anamount of about 28% and the fourth herb is present in an amount of about14%.

In yet a further embodiment of this invention, the composition comprisesfive different herbs, one of which is each selected from Herb A, Herb B,Herb C, Herb D or Herb E, each of the five herbs are present in anamount from about 5% to about 35%. In a further example of thisembodiment, each of the five herbs are present in an amount from about10% to about 30%. In yet a further example of this embodiment, each ofthe five herbs are present in an amount from about 15% to about 25%. Ina further example of this embodiment, each of the five herbs are presentin an amount of about 20%.

In yet a further embodiment of this invention, the first four herbs areselected one from each of the group Herb A, Herb B, Herb C and Herb Dwhereas the fifth herb is selected from Herb E and the first four herbsare present in an amount from about 6% to about 38%, whereas the fifthherb is present at an amount from about 3% to about 19%. In a furtherexample of this embodiment, the first four herbs are present in thecomposition at an amount from about 12% to about 32%, and the fifth herbis present in an amount from about 6% to about 16%. In yet a furtherexample of this embodiment, the first four herbs are present in anamount from about 18% to about 26% and the fifth herb is present in anamount from about 9% to about 13%. In yet a further example of thisembodiment, the first four herbs are present at an amount of about 22%,whereas the fifth herb is present at an amount of about 11%.

In yet a further embodiment, the composition comprises six herbs. Thefirst five herbs are selected from the group consisting of Herb A, HerbB, Herb C, Herb D and Herb E, and the sixth herb is selected from Herb Fand the first five herbs are present in an amount from about 5% to about31% and the sixth herb is present in an amount from about 2.5% to about17.5%. In a further example of this embodiment, each of the first fiveherbs are present in an amount from about 10% to about 26%, and thesixth herb is present in an amount from about 5% to about 15%. In afurther example of this embodiment, the first five herbs are eachpresent in an amount from about 15% to about 21% and the sixth herb ispresent in an amount from about 7.5 to about 12.5%. In a further exampleof this embodiment, the first five herbs are present in an amount fromabout 18% and the sixth herb is present in an amount from about 10%.

In yet a further example of this embodiment, the first four herbs areselected from the group of Herb A, Herb B, Herb C or Herb D. The fifthherb is selected from Herb E and the sixth herb is selected from Herb F,wherein the first three herbs are each present in an amount from about5% to about 38%, the fifth herb is present in an amount from about 2.5%to about 19% and the sixth herb is present in an amount from about 1.75%to about 9.5%. In a further example of this embodiment, the first fourherbs are present in an amount from about 10% to about 33%. The fifthherb is present in an amount from about 5% to about 16.5% and the sixthherb is present in an amount from about 3% to about 8.25%. In yet afurther example of this embodiment, the first four herbs are present inan amount from about 15% to about 28%; herb five is present in an amountfrom about 7.5% to about 14.5% and the sixth herb is present in anamount from about 4.25% to about 7%. In yet a further example of thisembodiment, the first four herbs are present in an amount from about21%. The fifth herb is present in an amount from about 10.5% and thesixth herb is present in the amount from about 5.5%.

It is important to ensure that the herbs which are used according to thepresent invention are selected such that they contain only acceptablelevels of contaminants such as metals or pesticides. Various regions ofChina have been surveyed and it was found that the component herbs canbe harvested from the Guangxi, Hunan, Liaoning, Anhui, Hebei and Jiangsuregions of China during the summer and autumn months and no pesticidesare used. The plants are purchased dried and whole or parts of theseherbs are used in manufacturing.

The general manufacturing scheme is as follows: the herbs are eithersubjected to an aqueous extraction, the aqueous extract is then filteredif necessary to remove large particles, the aqueous extract is thendried to a powder. Alternatively, it is possible to use the herbsdirectly by grinding to a powder. The powdered herbs are then used inthe production of the therapeutic in a variety of forms foradministration.

Any suitable mode of delivery can be used according to the presentinvention. For example the composition of the present invention can bedelivered orally by a pill, tablet, drink, candy or paste. Thecomposition can also be delivered as a transdermal patch, by inhalationor suppository. Delivery of the composition as an injectable is alsopossible, according to the present invention. Therefore, the compositioncan be administered as a therapeutic agent or as a dietary supplement.

In one embodiment of the present invention, tablets are formulated into0.3 g tablets. A typical daily dosage is about 1.2 to 6 g/day based onthe body weight and/or severity of the condition.

According to the present invention the compositions are useful for avariety of therapeutic treatments. In one embodiment of the presentinvention the compositions are useful for the prevention or treatment ofcancers.

According to one embodiment of the present invention, the compositioncomprises additional therapeutic agents. Examples of such agents caninclude, but are not limited to, chemotherapeutic agents.

As will be apparent to those skilled in the art in light of theforegoing disclosure, may alterations and modifications are possible inthe practice of this invention without departing from the spirit orscope thereof. Accordingly, the scope of the invention is to beconstrued in accordance with the substance defined by the followingclaims.

1-8. (canceled)
 9. A composition comprising a mixture of at least threedifferent herbs selected from the group consisting of Herb A, Herb B,Herb C, Herb D, Herb E and Herb F, wherein Herb A is selected from thegroup consisting of: Sophora tonkinensis Belamcanda chinensisScrophularia ningpoensis. Isatis tinctoria Isatis indigotica andBaphicacanthus cusia; Herb B is selected from the group consisting of:Polygonum bistorta Polygonum lapidosum. Polygonum viviparum Polygonummanshuriense Polygonum alopecuroides Polygonum sphaerostachyumAndrographis paniculata Taraxacum mongolicum and Chrysanthemun indicum;Herb C is selected from the group consisting of: Prunella vulgariArtemissia capillaris Gardenia jasminoides Rosa rugosa and Lophatherumgracile; Herb D is selected from the group consisting of: Sonchusbrachyotus Patrinia scabiosaefolia Patrinia villosa Sonchus arvensisThlaspi arvense Portulaca oleracea and Pulsatilla chinensis; Herb E isselected from the group consisting of: Dictamnus dasycarpus Kochiascoparia Sophora flavescens and Heydyotis diffusa; and Herb F isselected from the group consisting of: Dioscorea bulbifera Panaxnotoginseng Bletilla striats Nelumbo nucifers Polygonum bistortaCephalanoplos segetum Cirsium japonicum. Sophora japonica. Typhaangustfolia and Rubia cordifolia.; and wherein the composition does notcomprise more than 5 herbs selected from the group consisting of Sophoratonkinesis (Sophora subprostata), Polygonum bistorta, Prunella vulgaris,Sonchus brachyotus, Dictamnus dasycarpus and Dioscorea bulbifera. 10.The composition of claim 9, wherein one of each three herbs is differentfrom at least one of: Herb A, Herb B, Herb C, Herb D, Herb E and Herb F.11. The composition of claim 9, wherein Herb A is selected from thegroup consisting of: Belamcanda chinensis Scrophularia ningpoensis.Isatis tinctoria Isatis indigotica and Baphicacanthus cusia; Herb B isselected from the group consisting of: Polygonum lapidosum. Polygonumviviparum Polygonum manshuriense Polygonum alopecuroides Polygonumsphaerostachyum Andrographis paniculata Taraxacum mongolicum andChrysanthemun indicum; Herb C is selected from the group consisting of:Artemissia capillaris Gardenia jasminoides Rosa rugosa and Lophatherumgracile; Herb D is selected from the group consisting of: Patriniascabiosaefolia Patrinia villosa Sonchus arvensis Thlaspi arvensePortulaca oleracea and Pulsatilla chinensis; Herb E is selected from thegroup consisting of: Kochia scoparia Sophora flavescens and Heydyotisdiffusa; and Herb F is selected from the group consisting of: Panaxnotoginseng Bletilla striats Nelumbo nucifers Cephalanoplos segetumCirsium japonicum. Typha angustfolia and Rubia cordifolia.
 12. Thecomposition of claim 9, wherein the composition comprises three herbs,one of which is selected from each of Herb A, Herb B, Herb C, Herb D orHerb E and wherein each is present in an amount from about 9% to about57%.
 13. The composition of claim 9, wherein the composition comprisesfour herbs, one of which is selected from each of Herb A, Herb B, HerbC, Herb D or Herb E, and wherein each is present in an amount from about6% to about 43%.
 14. The composition of claim 9, wherein the compositioncomprises four herbs, the first three are selected from the groupconsisting of Herb A, Herb B, Herb C and Herb D and are present in anamount from about 7% to about 57% and the fourth is selected from Herb Eand is present in an amount from about 3.5% to about 28.5%.
 15. Thecomposition of claim 9, wherein the composition comprises five herbs,one of which is selected from each of Herb A, Herb B, Herb C, Herb D orHerb E, and wherein each is present in an amount from about 5% to about35%.
 16. The composition according to claim 9, wherein the compositioncomprises five herbs, and wherein the first four herbs are selected fromthe group consisting of Herb A, Herb B, Herb C and Herb D and arepresent in an amount from about 6% to about 38% and the fifth herb isselected from Herb E and is present in an amount from about 3% to about19%.
 17. The composition according to claim 9, wherein the compositioncomprises six herbs, and wherein the first five herbs are selected fromthe group consisting of Herb A, Herb B, Herb C, Herb D and Herb Ewherein the herbs are present in an amount from about 5% to about 31%and the sixth herb is selected from Herb F and is present in an amountfrom about 2.5% to about 17.5%.
 18. The composition according to claim9, wherein the composition comprises six herbs, and wherein the firstfour herbs are selected from the group consisting of Herb A, Herb B,Herb C and Herb D and are present in an amount from about 5% to about38% and the fifth is selected form Herb E and is present in an amountfrom about 2.5% to about 19% and the sixth herb is selected from Herb Fand is present in an amount from about 1.75% to about 19%.